He was an assistant professor of psychology at the University of Maine from 1987 to 1991. In Harrington v. Almy the United States Court of Appeals for the First Circuit found that a penile plethysmograph test ordered to be administered by O'Donohue as a precondition of employment was a violation of a Maine police officer's rights under the Fourteenth Amendment to the United States Constitution.[3][4] In 1996, he was appointed Director of Sexual Assault Prevention and Counseling Services at University of Nevada, Reno. O'Donohue founded CareIntegra with colleagues in 1999 and serves as CEO.

O'Donohue has been critical of the use of forensic evaluations administered to litigants in child custody disputes. He told the New York Times, "Psychologists don't have the knowledge to do what they attempt to do when they do custody evaluations," adding that custody decisions are more about competing values than scientific findings when determining a child's best interest.[5]